Infantile Autistic Syndrome Disorders (ASD) include a wide range of abnormalities including a genuine incapacity to organise affective relations, behavioural anomalies in reciprocal social interactions, verbal and non verbal communication, limited interest in the surrounding environment associated with stereotyped movements and repetitive plays (Kanner, 1943; Levy and Hyman, 1993; Levy and Hyman, 2005; Adrien et al., 2001; Blanc et al., 2005; Bourreau et al., 2009). Research to date indicates that a genetic predisposition may play a role in the disease but one or more environmental factors must be in place for symptoms to occur including environmental contaminants and possibly maternal exposures during gestation (Persico and Bourgeron, 2006; Bourgeron, 2009; Patterson, 2002). It is suggested that genetic and environmental hazards will alter developmental programs leading to cortical and/or sub-cortical malformations and the formation of misplaced/ misconnected neuronal ensembles. The first symptoms occur before 3 years of age with most likely an earlier origin. There is at present no efficient biological/pharmaceutical treatment to ASD.
Brain maturation is associated with a developmental sequential expression of voltage gated, receptor synapse driven channels and brain patterns (Spitzer et al., 1994; Ben Ari et al., 2007). The developmental shifts of the actions of the inhibitory transmitter GABA is but one example of these changes. Immature neurons have a higher (Cl−)I than adults leading to paradoxical excitatory actions of GABA (Ben Ari, 2002; Ben Ari et al., 2007). This is due to an early expression of the co-transporter NKCC1 that imports chloride and a late operation of KCC2 that export chloride form neurons (Kahle and Staley, 2008; Rivera et al., 1999; Dzhala et al., 2005; Delpire et al., 1999; Delpire, 2000; Li et al., 2002). In addition, the regulation of (Cl−)I is dynamic and altered by even brief episodes of enhanced activity (Balena and Woodin, 2008; Fiumelli et al., 2005; Fiumelli and Woodin, 2007; Woodin et al., 2003) and more persistently by a variety of insults, lesions, seizures and neurological disorders (Khalilov et al., 2003; Khalilov et al., 2005; Cohen et al., 2002; Huberfeld et al., 2006; Huberfeld et al., 2007). Consequently, diuretic agents that reduce (Cl−)I constitute novel antiepileptic and neuro-protective agents (Dzhala et al., 2005; Nardou et al., 2009; Kahle et al., 2008; Payne et al., 2003). In keeping with this, clinical tests are presently being conducted to that aim in infantile epilepsies.
Bumetanide (Bum) (Cohen, 1981; Feit, 1981) is a classical diuretic that selectively antagonises the co-transporter NKCC1—thereby reducing (Cl−)I (Delpire et al., 1999; Delpire and Mount, 2002). Bum has been extensively utilised in adults since 1975 and in children since 1986 and its pharmacokinetic in adults and children and its side effects are well known (Lopez-Samblas et al., 1997; Sullivan et al., 1996; Witte et al., 1986; Marshall et al., 1998). Bum is used in acute (oedema following head trauma) and long term conditions including broncho-pulmonary dysplasia, nephritic syndromes or heart congestions (O'Donnell et al., 2004; Mackie et al., 1986; Sullivan et al., 1996) and has been recently reported to reduce seizure severity in a case report (Kahle et al., 2009). The use of Bum is safe provided that it is accompanied with continuous clinical and biological surveillance notably in children.
The inventors have now investigated in 5 autistic infants the effects of bum with ongoing clinical and biological surveillance. They were selected with no a priori from a large group of ASD children placed in institutions or at home to provide a variety of cases. The diuretic was administered (1 mg/24 h, 0.5 mg twice a day) and the treatment continued for 3 months, a minimal duration considered to be sufficient for an evaluation of the effects on IAS. We report a significant improvement of the IAS manifestations in the 5 children. These observations call for wide range screening of the use of Bum in IAS and more generally in autism.